Effect of preoperative intranasal insulin on postoperative delirium in adult surgical patients: a systematic review, meta-analysis, and trial sequential analysis

Postoperative delirium (POD) is a frequent and serious complication, especially in older adults and high-risk surgical patients. Intranasal insulin has emerged as a potential neuroprotective intervention, possibly modulating neuroinflammation and preserving cognitive function. This study aimed to evaluate the efficacy and safety of preoperative intranasal insulin in reducing POD incidence. A systematic review and meta-analysis were conducted according to PRISMA guidelines. PubMed, Embase, and the Cochrane Library were searched through March 2025 for randomized controlled trials (RCTs) comparing intranasal insulin versus placebo in adult surgical patients. The primary outcome was the incidence of POD. Secondary outcomes included inflammatory biomarkers (IL-6, TNF-α, CRP), glucose levels, and insulin resistance (HOMA-IR). Odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using random-effects models. Trial Sequential Analysis (TSA) was also performed. Eight RCTs from China involving 888 patients (481 intranasal insulin, 407 placebo) were included. Intranasal insulin significantly reduced the risk of POD (OR 0.24; 95% CI 0.17 to 0.34; p < 0.001; I2 = 0%). TSA confirmed the robustness of this finding. Significant reductions in IL-6 (MD -2.52; 95% CI -3.45 to -1.58) and TNF-α (MD -5.02; 95% CI -8.67 to -1.36) were observed. No significant differences were found in serum or CSF glucose, or HOMA-IR. No hypoglycemia or serious adverse events were reported. Preoperative intranasal insulin is a safe and effective strategy to reduce POD, likely through central anti-inflammatory mechanisms, without compromising glycemic stability. Question: Is preoperative intranasal insulin effective in reducing the incidence of postoperative delirium in adult surgical patients? Findings: Intranasal insulin significantly reduced postoperative delirium and systemic inflammation without affecting glycemic stability. Meaning: Preoperative intranasal insulin is a safe and promising strategy for perioperative neuroprotection in high-risk patients.